Cernan traveled into space three times; as pilot of Gemini 9A in June 1966, as lunar module pilot of Apollo 10 in May 1969, and as commander of Apollo 17 in December 1972, the final Apollo lunar landing. Cernan was also a backup crew member of the Gemini 12, Apollo 7 and Apollo 14 space missions.

Cernan was originally selected with Thomas Stafford as backup pilot for Gemini 9. When the prime crew of Elliot See and Charles Bassett was killed in the crash of NASA T-38A "901" (USAF serial 63-8181) at Lambert Field on February 28, 1966, the backup crew became the prime crew—the first time in NASA history this happened.[7] Gemini 9A encountered a number of problems; the original target vehicle exploded during launch and the planned docking with a substitute target vehicle was made impossible by the failure of a protective shroud to separate after launch.[7] The crew, however, performed a rendezvous that simulated procedures that would be used in the Apollo 10 mission; the first optical rendezvous and a lunar-orbit-abort rendezvous. Cernan performed the second American EVA—the third-ever spacewalk—but overexertion caused by a lack of limb restraints prevented testing of the Astronaut Maneuvering Unit and forced the early termination of the spacewalk.[7] Cernan was also a backup pilot for the Gemini 12 mission.[8]

Cernan was selected for the lunar module pilot position on the backup crew for Apollo 7—although that flight carried no lunar module.[9] Standard crew rotation put him in place as the Lunar Module Pilot on Apollo 10—the final dress rehearsal mission for the first Apollo lunar landing—on May 18–26, 1969. During the Apollo 10 mission, Cernan and his commander, Tom Stafford, piloted the Lunar Module Snoopy in lunar orbit to within 8.5 nautical miles (15.7 km) of the lunar surface, successfully executing every phase of a lunar landing up to final powered descent and providing NASA planners with critical knowledge of technical systems and lunar gravitational conditions to enable Apollo 11 to land on the Moon two months later.

Cernan turned down the opportunity to walk on the Moon as Lunar Module Pilot of Apollo 16, preferring to risk missing a flight for the opportunity to command his own mission.[10] Cernan moved back into the Apollo rotation as commander of the backup crew of Cernan, Ronald E. Evans, and Joe Engle for Apollo 14, putting him in position through normal crew rotation to command his own crew on Apollo 17. Escalating budget cutbacks for NASA, however, brought the number future lunar missions into question. After the cancellation of Apollo 15 in its original H class profile and Apollo 19 in September 1970, pressure from the scientific community to shift Harrison Schmitt, the sole professional geologist in the active Apollo roster of astronauts, to the crew of Apollo 17, the final scheduled Apollo mission, mounted. In August 1971, NASA named Schmitt as the lunar module pilot for Apollo 17, which meant the original LM pilot Joe Engle never had the opportunity to walk on the Moon. Cernan fought to keep his crew together; given the choice of flying with Schmitt as LMP or seeing his entire crew removed from Apollo 17, Cernan chose to fly with Schmitt. Cernan eventually came to have a positive evaluation of Schmitt's abilities; he concluded that Schmitt was an outstanding LM pilot while Engle—notwithstanding his outstanding record as an aircraft test pilot—was merely an adequate one.[11]

Cernan's role as commander of Apollo 17 closed out the Apollo program's lunar exploration mission with a number of record-setting achievements. During the three days of Apollo 17's surface activity (Dec. 11-14, 1972), Cernan and Schmitt performed three EVAs for a total of about 22 hours of exploration of the Taurus–Littrow valley. Their first EVA alone was more than three times the length astronauts Neil Armstrong and Buzz Aldrin spent outside the LM on Apollo 11. During this time Cernan and Schmitt covered more than 35 km (22 mi) using the Lunar Rover and spent a great deal of time collecting geologic samples (including a record 34 kilograms (75 lb) of samples, the most of any Apollo mission) that would shed light on the Moon's early history. Cernan piloted the rover on its final sortie, recording a maximum speed of 11.2 mph (18.0 km/h), giving him the unofficial lunar land speed record.[12]

As Cernan prepared to climb the ladder for the final time, he spoke these words, currently the last spoken by a human being standing on the lunar surface:

Bob, this is Gene, and I'm on the surface; and, as I take man's last step from the surface, back home for some time to come – but we believe not too long into the future – I'd like to just (say) what I believe history will record: that America's challenge of today has forged man's destiny of tomorrow. And, as we leave the Moon at Taurus–Littrow, we leave as we came and, God willing, as we shall return, with peace and hope for all mankind. Godspeed the crew of Apollo 17.

Eugene Cernan at a memorial service for Neil Armstrong September 13, 2012

In 1976, Cernan retired from the Navy with the rank of captain and went from NASA into private business, becoming Executive Vice President of Coral Petroleum Inc. before starting his own company, The Cernan Corporation, in 1981.[5] From 1987 he was a contributor to ABC News and the weekly segment of its Good Morning America program titled "Breakthrough", which covered health, science, and medicine.[14]

In 1999, with co-author Donald A. Davis, he published his memoir The Last Man on the Moon, which is about his naval and NASA career. He is featured in the space exploration documentary In the Shadow of the Moon. in which he said, "truth needs no defense" and "nobody can take those footsteps I made on the surface of the Moon away from me".[15] Cernan also contributed to the book of the same name.

Cernan paired his criticism of the cancellation of Constellation with expressions of skepticism about Commercial Resupply Services (CRS) and Commercial Crew Development (CCDev), NASA's planned replacements for that program's role in supplying cargo and crew to the International Space Station. Such companies, Cernan warned, "do not yet know what they don't know." Cernan's view of commercial space companies—in particular SpaceX, which participates in both programs—underwent a positive shift after being debriefed by SpaceX venture capitalist Steve Jurvetson as part of his effort to obtain the signatures of nine Apollo astronauts on a photograph meant as a gift to SpaceX founder Elon Musk to commemorate the first successful SpaceX cargo mission to the ISS in 2012. Eventually, Cernan was won over and signed the photograph; "As I told him these stories of heroic entrepreneurship, I could see his mind turning." Jurvetson wrote; "He found a reconciliation: 'I never read any of this in the news. Why doesn't the press report on this?'" [17]

In 2016, Cernan appeared in the documentary The Last Man on the Moon, made by British filmmaker Mark Craig and based on Cernan's 1999 memoir of the same title.[18] The film received the Texas Independent Film Award from Houston Film Critics Society and the Movies for Grownups Award from AARP The Magazine.[19][20]

Cernan was married twice and had one daughter. His first wife was Barbara Jean Atchley, a flight attendant for Continental Airlines, who he married in 1961. They had one daughter, Tracy (born in 1963). The couple separated In 1980 and divorced in 1981. They remained friends.[21] His second marriage was to Jan Nanna Cernan, which lasted for nearly 30 years from 1987 until his death. Cernan gained two step-daughters, Kelly and Danielle.[22]

Orbital ATK announced the naming of its Cygnus CRS OA-8E Cargo Delivery Spacecraft the S.S. Gene Cernan in honor of Cernan in October, 2017.[32] The S.S. Gene Cernan successfully launched to the International Space Station on November 12, 2017.[33]

A popular belief is that Cernan wrote his daughter's initials on a rock on the Moon. The story, and Cernan's relationship with his daughter, was later adapted into "Tracy's Song" by pop-rock band No More Kings. The story is inaccurate; Cernan did not write his daughter's initials on a rock. He states in the 2014 documentary The Last Man on the Moon that he wrote them in the lunar dust as he left the rover to return to the LEM and Earth.[37] The true story of leaving the initials on the lunar surface was prominently mentioned in an episode (Season 3 Episode 20: The Last Walt) of Modern Family.[38]